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Suspected off-label infringing uses do not equal inducement

On May 6, 2015, the U.S. Court of Appeals for the Federal Circuit issued its full opinion affirming the U.S. District Court for the District of Delaware’s denial of Takeda Pharmaceutical’s motion for preliminary injunction seeking to enjoin the launch of Mitigare® (colchicine), a gout treatment drug. Takeda Pharmaceuticals v. West-Ward Pharmaceutical Corp., et al., 785 F.3d 625 (Fed. Cir. 2015).

Background

Colchicine itself has been used as a medication for centuries, in many cultures and civilizations, and is not covered by Takeda’s patents. Takeda’s patents are directed toward methods of treating acute gout flares and methods of administering colchicine for prophylaxis of gout in patients also taking certain drug inhibitors.

In 2010, Hikma Pharmaceuticals submitted an new drug application (NDA) under § 505(b)(2) of the Hatch-Waxman Act, seeking U.S. Food and Drug Administration (FDA) approval to market a colchicine product for prophylaxis of gout flares. Hikma received approval and launched Mitigare on October 3, 2014, and planned to release an authorized generic as early as October 10, 2014.

On October 3, 2014, Takeda sued West-Ward Pharmaceutical and Hikma, alleging induced infringement based on the Mitigare label. On October 9, 2014, the Delaware district court granted Takeda a temporary restraining order (TRO) restraining Hikma from selling Mitigare and launching its planned generic. On November 4, 2014, the district court denied Takeda’s motion for a preliminary injunction. The court held that Takeda had not shown a likelihood of succeeding on its induced infringement claims. The court also found Takeda had not demonstrated that it would be irreparably harmed if Hikma launched Mitigare and the authorized generic. The court also ordered that, if Takeda took an immediate appeal, the court would extend the TRO pending the appeal. Takeda appealed. Following oral argument on January 9, 2015, the Federal Circuit affirmed the district court’s denial of the preliminary injunction and vacated the TRO; the Federal Circuit noted in its decision that an opinion would be forthcoming.

ANDAs and Paper NDAs May be Granted for Un-patented Uses

Pursuant to the Hatch-Waxman Act, an abbreviated new drug application (ANDA) or paper NDA filer must submit one of several kinds of patent certifications, including a Paragraph IV certification of non-infringement and/or patent invalidity. Hikma filed a paper NDA pursuant to 21 U.S.C. § 355(b)(2). Hikma did not file a Paragraph IV certification, because it relied on prior FDA findings of safety and efficacy concerning colchicine and did not seek FDA approval for a use covered by Takeda’s patents. The Federal Circuit confirmed that a “single drug could have more than one indication and yet that an ANDA applicant could seek approval for less than all those indications.”

Mere Knowledge of Possible Off-Label Uses Is Not Inducement

Hikma did not seek FDA approval to market Mitigare for treatment of acute gout flares. Its label stated that Mitigare was “indicated for prophylaxis” and that “the safety and effectiveness of it for acute treatment of gout flares during prophylaxis has not been studied.” The label also stated “if you have a gout flare while taking [Mitigare], tell your healthcare provider.” Takeda argued that the last statement induced infringement because the physician prescribing Mitigare as a prophylaxis would likely tell the patient to use Mitigare to treat the acute flare. The Federal Circuit rejected Takeda’s argument.

The court found that for a drug label to induce infringement, it “must encourage, recommend or promote infringement. The mere existence of direct infringement by physicians, while necessary to find liability for induced infringement, is not sufficient for inducement.” The court also noted that “it is well-established that mere knowledge of possible infringement by others does not amount to inducement; specific intent and action to induce infringement must be proven.” The court went on to find that the requirement of inducing acts is “particularly important in the Hatch-Waxman context because the statute was designed to enable the sale of drugs for non-patented uses even though this would result in some off-label infringing uses.”

The Federal Circuit rejected Takeda’s argument that Mitigare’s label instruction (to tell your health care provider if you have gout flares) would inevitably lead physicians contacted about gout flare to simply increase the patient’s dose of Mitigare to treat the flare. The court found that “vague label language cannot be combined with speculation about how physicians may act to find inducement.” The court also found that, despite its physician affidavits, Takeda had not presented sufficient evidence that the Mitigare label would necessarily lead doctors to prescribe an off-label use of the drug to treat gout flares.

Takeda Failed to Show Direct Infringement of the Drug Inhibitor Patents

With respect to the drug inhibitor patents, the Federal Circuit similarly upheld the district court’s finding that Takeda had not shown a likelihood of succeeding on its direct infringement claims. The Mitigare label warns patients that co-administration of colchicine and certain inhibitors “have been reported to lead to colchicine toxicity” and that, if co-administration is necessary, “the dose of Mitigare should be reduced and the patient should be monitored carefully for colchicine toxicity.” The court rejected Takeda’s argument that the label language constituted inducement as a doctor would need to determine whether co-administration was necessary and then would follow the patented methods if they determined it was necessary. The court affirmed the district court’s finding that Takeda failed to provide sufficient evidence that any doctor had actually practiced the methods of the drug inhibitor patent, a prerequisite for indirect infringement. The court also affirmed the district court findings that the label instructions for controlling against toxicity would not have instructed doctors to practice the patented methods.

Judge Newman Dissented

Judge Pauline Newman dissented, arguing that the majority erred in “ruling that the provider of a known drug product, with knowledge that it is likely to be used in direct infringement, can never be liable for induced infringement.” She pointed out that the issues in the case were fact specific and not amenable to final disposition at a preliminary injunction hearing. Judge Newman charged that the panel opinion “presents an incomplete picture of the facts and the law and ignores the public interest in the development of improved methods of treatment.” She argued that the majority decision stated a general rule “that provides easy avoidance of patents on new uses and improvements” by allowing drug developers to simply omit patented methods of treatment from its label.

Judge Newman disagreed with the majority’s interpretation of Hatch-Waxman as allowing the sale of drugs for non-patented uses even if some off-label infringing use was likely; “[t]he Hatch-Waxman Act is not designed to enable off-label uses, whether or not they are infringing.” She argued that the trier of fact must have the opportunity to evaluate the evidence concerning doctor’s likely response to the Hikma label’s instruction to inform the prescribing physician of an acute gout flare. This type of evidence is “highly relevant to whether infringement is deemed induced.” Purposefully avoiding a patented use on the label where a manufacturer knows doctors will prescribe the drug for an off-label-infringing use may lead to a determination of inducement.

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